Diabetes is a significant health problem worldwide. Present estimates indicate that diabetes is becoming an increasingly prevalent disease which is doubling every 10-15 years, and that by the year 2010 over 250 million people will be afflicted. P. Zimmet, et al., Diabetes global estimates and projections, ed. 1994-2010 (1994). Most individuals with idiopathic diabetes can be categorized as having insulin-dependent diabetes mellitus (type I diabetes) or noninsulin-dependent diabetes mellitus (type II diabetes). Although the etiologies and clinical manifestations of these two syndromes differ, it has become increasingly clear that a critical lesion in many of the subgroups under these large classifications is at the level of the β-cell. Mandrup-Poulsen, Biochem Pharmacol 66:1433-40 (2003); Halban, et al., Diabetologia 47:581-89 (2004).
Although new treatment protocols have had a significant impact on life expectancy and quality of life of individuals with either form of diabetes, there still remains no cure. Insulin treatment for absolute or relative insulin-deficiency cannot adequately compensate for the loss of physiological insulin secretion. Intra-hepatic islet transplantation is a promising strategy in connection with type I diabetes. Unfortunately, this approach has been plagued by the loss of function and viability of islet cells during isolation and in the early transplantation period. Weir, et al., Arch. Med. Res. 36:273-80 (2005). This has caused a dramatic increase in the number of islets required for transplantation, which has significantly impacted the amount of islets available for transplant. Additionally, this problem has contributed greatly to the graft failure that has been seen in most transplant recipients over time. See, Gaglia, et al., Arch. Med. Res. 36:273-80 (2005); Weir, et al., supra. Therefore, there is a belief that functional loss and death of β-cells play a predominant role in the pathogenesis of both types of diabetes and in the failure of islet transplants.
Inflammatory bowel disease (IBD), more common forms of which include Crohn's disease and ulcerative colitis, affects a staggering number of people in developed countries, estimated at around 0.1% of the population. As a group, these disorders are characterized by unrelenting inflammation of the lower gastrointestinal tract leading to periodic and sometimes chronic bouts of diarrhea, profound abdominal distress, malnutrition, and other symptoms. Pathologically, the colonic mucosa of afflicted individuals is overtly disrupted and shows signs if intense inflammation with invasion of commensal organism from the intestinal lumen into the mucosal wall. The cause of IBD remains unknown, although it is believed that both genetics and environmental factors make a significant contribution.
Ischemic heart disease (IHD) continues to be a leading cause of death and of health care expense in the United States. Although there are myriad risk factors for IHD (e.g., smoking, hypertension and obesity). In diabetic and obese prediabetic patients, there is a growing consensus about the growth of coronary collaterals being impaired. See, Abaci, et al., Circulation 99:2239-42 (1999); Kornowski, Coron. Artery Dis. 14:61-4 (2003); Turhan, et al., Coron. Artery Dis. 16:281-85 (2005); Waltenberger, Cardiovasc. Res. 49:554-60 (2001). This is critical because the presence of well-developed coronary collateral circulation makes an important impact on the morbidity and mortality associated with coronary disease. See, Hansen, Am. Heart J. 117:290-95 (1989). Because 30-40% of patients demonstrate an absence of a coronary collateral circulation and are at much higher risk of developing complications in the event of a coronary occlusion, new therapies are essential to protect these individuals.
Acute lung injury and the acute respiratory distress syndrome (ALI/ARDS) are syndromes of acute onset arising with non-cardiogenic pulmonary edema development, manifest as bilateral infiltrates on the chest radiograph coupled to acute hypoxic respiratory failure. Currently, it is estimated that 16%-18% of all ICU patients develop ALI/ARDS producing 6,368,000 hospital days per year in health care costs. The mortality estimates of patients suffering from this syndrome are still 30-50%. Recent estimates of incidence in the United States are around 190,000 cases of ALI and ARDS per year. These numbers are actually projected to rise with the aging of the population and the projected increase in severe sepsis cases, which is the most common cause of ALI/ARDS. See, Ware, et al., N. Eng. J. Med. 353:2788-96 (2005).
Bronchopulmonary dysplasia (BPD) is one such example of an acute lung disease that occurs primarily in preterm infants who require supplemental oxygen. Although the advent of surfactant therapy and use of high frequency low tidal volume ventilator approaches have improved the survival rates of extremely low birth weight infants, significant morbidity and mortality continues to be associated with BPD. In a recent review of clinical data, BPD was shown to be the most costly disease per child and second only to asthma in overall costs. See, Ireys, et al., Pediatrics 100:197-204 (1997). Due to the high rate of premature births and the recent increase in multiple births, BPD is rapidly becoming a common and costly healthcare challenge.
It was estimated that in 2005, approximately 18,500 new cases of primary central nervous system (CNS) tumors would be diagnosed and 12,760 deaths from primary CNS tumors would occur in the United States. See, Jemal, et al., Can. Cancer. J. Clin. 53:5-26 (2003). The majority of these deaths result from malignant gliomas. The optimum therapeutic modality presently consists of surgical tumor resection followed by radiotherapy and chemotherapy. The relationship between increased survival and increased radiotherapy dose was demonstrated by Walker, et al, Int. J. Radiat. Oncol. Biol. Phys. 5:1725-31 (1979). However, the total dose of radiation that can be administered safely is limited by the risk of normal brain morbidity. This can lead to devastating functional deficits several months to years after irradiation. See, Sheline, et al., Int. J. Radiat. Oncol. Biol. Phys. 6:1215-28 (1980); Leibel, et al., Int. J. Radiat. Oncol. Biol. Phys. 17:1129-39 (1989). Thus, in practice, the radiation dose applied to the brain must be limited. The need to both understand and minimize the side effects of brain irradiation is enhanced by the ever-increasing number of patients with secondary brain metastases that require treatment with large field or whole brain irradiation (WBI). Approximately 200,000-250,000 patients will be diagnosed with brain metastases in 2005, making this the second most common site of metastatic cancer as well as the most common neurological manifestation of cancer. Brain metastases are more common in incidence than newly diagnosed lung, breast, or prostate cancer. Currently, approximately 175,000 cancer patients per year receive large field or WBI. Yet, at the present time, there are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies.